We propose to develop the macromolecular modeling needed for a fundamental molecular understanding of how electrically charged polymer molecules move through protein channels. Stimulated by prospects of direct high-speed detection of sequences in single polynucleotide molecules, and of stochastic sensing of single macromolecular analytes, very exciting single-molecule electrophysiology experiments have recently been reported. The results of these experiments are very puzzling and require an understanding of polymer physics, in combination with descriptions of chemical specificities. We propose to implement polymer physics concepts valid at large length and time scales, in conjunction with Brownian Dynamics simulations accounting for details at smaller length and time scales. The present proposal addresses a fundamental understanding of (1) how DNA/RNA molecules move through alpha-hemolysin channels under an electric field and computation of ionic current of channels with macromolecular transport, (2) origin of discrete conductance states and conformations of polymer tethers engineered into protein pores, and (3) development of coarse-grained models for RNA-carrying transport factors and their transport through nuclear pore complexes. Our unique combination of theory, simulations, and collaborations with active experimentalists, will have a direct and profound impact on understanding of signal transduction, high-speed sequencing of DNA/RNA and proteins, screening of biological warfare agents, pharmaceutical diagnostics, and macromolecular aspects of diseases and their control.